The generation of memory lymphocytes is essential for protection against many infectious pathogens and is the goal of vaccination. Although much has been learned regarding the generation and quantification of memory T cells, how memory cell populations are regulated in terms of migratory abilities and functional differentiation in vivo remain subjects of great interest and importance. The patrolling of mucosal tissues by memory T cells is critical to protection against infection, since these sites are in close proximity to the environment. Our results suggest that microbe-specific CD8 and CD4 memory T cells exhibit tissue-specific differences in the intestinal mucosa and other non-lymphoid tissues. However, whether the generation of memory cells in a particular tissue occurs in lymphoid tissue associated with that site is unknown. Also, whether memory cells in a given tissue are part of a larger recirculating pool or resident in that site has not been determined. Moreover, whether memory cells can modify their functional behavior upon entry into a particular tissue remains unclear. Thus, the studies proposed will test the hypothesis that the site of initial T cell activation regulates homing molecule expression and will examine the role of such molecules in memory cell migration to the intestinal mucosa and elsewhere. The aims of the proposal are: Aim 1. To determine whether the site of activation of naive or memory T cells directs the pattern of homing molecule expression. Studies will test the hypothesis that the pattern of homing molecule expression by T cells responding to Listeria monocytogenes infection is dependent on the site of antigen encounter. Aim 2. To determine the migratory abilities of microbe-specific memory T cells in vivo. Experiments will compare the efficiency of migration of microbe-specific CD8 versus CD4 memory T cells into the intestinal mucosa and the functional consequences of migration will be assessed. Aim 3. To determine the molecular requirements for migration of effector and memory antimicrobial T cells to the intestinal mucosa. Whether candidate homing molecules are involved in primary and memory cell migration to the intestinal mucosa will be examined using T cells deficient in these molecules. Overall, these studies will provide significant new information regarding the population dynamics of T cell memory generation and migration in vivo in response to infection.